ИСТИНА

Background & Objectives: Heterogeneous mismatch repair (hMMR) status, noted in colorectal and endometrial cancers, remains underexplored in gastric cancer (GC). This study investigates hMMR prevalence in GC and its clinicopathological correlates, aiming to elucidate its role in tumor progression and potential implications for immunotherapy responsiveness. Methods: We analyzed surgical specimens from 159 GC patients (2010–2018) without neoadjuvant therapy. Immunohistochemistry targeted MMR proteins (MSH2 [79H11], MSH6 [EP49], MLH1 [ES05], PMS2 [EP51]). hMMR was defined as ≥20% unstained areas amid strongly stained regions, classified per Joost et al. (modified) as intraglandular, clonal, or mixed patterns. MMR status was correlated with sex, age, tumor site, macroscopic type, size, histologic subtype, differentiation grade, vascular invasion, TNM stage, and clinical stage. Statistical analysis used χ2 or Fisher’s exact tests in Statistica 12.5.192.7 (p<0.05). Results: hMMR was observed in 37/159 cases (23.3%), MMR-proficient in 104 (65.4%), and MMR-deficient in 12 (7.6%). Among MMR-deficient cases, 6 (3.8%) exhibited hMMR of retained markers (MMR-deficient/hMMR). Dual-marker heterogeneity, predominantly MLH1/PMS2 (n=17), was common. hMMR was enriched in papillary vs. discohesive subtypes (p=0.031), while MMR-proficient tumors prevailed in the latter. Both hMMR and MMR-deficient/hMMR statuses were linked to intestinal subtype (p=0.006, p=0.036) and well-differentiated tumors (p<0.05, p=0.014). hMMR predominated in macroscopic types 3–4 vs. MMR-deficient/hMMR (p<0.001). No significant correlations emerged with sex, age, or tumor size. Conclusion: hMMR affects 23.3% of GC cases, often involving MLH1/PMS2, and correlates with papillary and intestinal subtypes, well-differentiated tumors, and advanced macroscopic types, suggesting clonal evolution with implications for prognosis and immunotherapy.